The ARROW trial investigates Iodine-131-LNTH-1095, a novel PSMA-targeted radioligand, in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC) who previously progressed on abiraterone. Results indicate that the combination therapy met its primary endpoint, showing a significant PSA response: 62.9% of patients on the combination achieved a ≥50% decline in PSA, nearly doubling the 31.3% response observed in the enzalutamide-only group. However, radiographic progression-free survival (rPFS) showed no significant improvement, likely due to the trial’s design, which was not powered to confirm rPFS differences.

Iodine-131 differs from commonly used Lutetium-177 in radioligand therapy due to its higher energy emission and residual gamma decay. This feature can enhance cell-killing potential but also requires more rigorous safety protocols in certain institutions, making it potentially more challenging to administer. The ARROW trial’s safety profile was consistent with other PSMA radioligands, with manageable side effects like fatigue, mild gastrointestinal symptoms, and xerostomia.

Although the combination therapy showed promise, challenges exist in a crowded PSMA therapy market. Future research may consider adapting the 1095 construct for alpha emitters, such as actinium, which could provide potent cancer cell targeting while reducing toxicity in earlier-stage prostate cancer. Despite current limitations, ARROW supports the viability of Iodine-131-based PSMA targeting, offering a foundation for evolving targeted treatments in advanced prostate cancer.

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